CN112830884B - Salvianic acid a derivative, preparation method and medical application thereof - Google Patents
Salvianic acid a derivative, preparation method and medical application thereof Download PDFInfo
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- CN112830884B CN112830884B CN201911156886.8A CN201911156886A CN112830884B CN 112830884 B CN112830884 B CN 112830884B CN 201911156886 A CN201911156886 A CN 201911156886A CN 112830884 B CN112830884 B CN 112830884B
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- ZMMKVDBZTXUHFO-DDWIOCJRSA-M sodium;(2r)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate Chemical compound [Na+].[O-]C(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 ZMMKVDBZTXUHFO-DDWIOCJRSA-M 0.000 description 1
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 210000004026 tunica intima Anatomy 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
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- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract
The invention discloses a tanshinol derivative, a preparation method and medical application thereof. The tanshinol derivative has a structure shown in a formula I: The tanshinol derivative can be applied to medicines for protecting, treating and/or relieving cardiovascular and cerebrovascular diseases and orthopedic diseases of patients, and provides a new therapeutic medicine for preventing and treating cardiovascular and cerebrovascular diseases and orthopedic diseases.
Description
Technical Field
The invention belongs to the technical fields of pharmaceutical chemistry and medicines, and in particular relates to a tanshinol derivative containing amino acid, a preparation method and medical application thereof.
Background
The traditional Chinese medicine salvia miltiorrhiza (Salvia miltiorrhiza Bunge) has the effects of removing blood stasis, relieving pain, activating blood, dredging channels, clearing heart fire and relieving restlessness, is widely used for treating cardiovascular and cerebrovascular diseases such as angina pectoris, myocardial infarction, apoplexy and the like, and modern pharmacological research shows that the salvia miltiorrhiza has the effects of resisting atherosclerosis, improving blood circulation, resisting platelet adhesion and aggregation, eliminating oxygen free radicals in a body, improving hypoxia tolerance, improving coronary artery blood supply, protecting heart and brain cell injury and the like, and is one of the most common Chinese medicinal materials for treating coronary heart disease (T.O.Cheng, int.J.Cardiol.,2007, 121,9-22). The red sage root is used as a common traditional Chinese medicine for promoting blood circulation and removing blood stasis, and is also clinically used for treating various fractures and traumas, and the action mechanism of the red sage root mainly comprises the steps of improving local blood supply, improving blood microcirculation at fracture positions, promoting the growth of new capillaries at fracture positions, promoting the repair function of osteoblasts and osteoclasts, increasing the blood flow of tissues at fracture positions, increasing the supply and transportation of various tissues and repairing cells and factors in bones, and improving the biomechanical properties after fracture healing (Guo Y.B. and the like, J.Ethn pharmacol.,2014, 155, 1401-1416). In the traditional clinical practice, the red sage root is decocted in water to treat diseases, so that the effective components are mainly water-soluble components. Danshensu (DSS) is one of the most important water-soluble components, and is chemically named as D- (+) -3- (3, 4-dihydroxyphenyl) lactic acid, which is the basic chemical structure of various salvianolic acids. The structural formula is as follows:
Salvianic acid A has various pharmacological effects including antiinflammatory, antitumor, neuroprotection, myocardial protection, and immunity improving. Research shows that the salvianic acid A inhibits ischemia-reperfusion (I-R) induced myocardial injury through antioxidant and anti-lipid peroxidation characteristics, and protects the heart; modulating Bax, bcl-2 and caspase-3 expression enhances anti-myocardial apoptosis, thereby protecting against myocardial infarction (Wu l., et al Phytomedicine,2007, 14, 652-658); by inhibiting monocyte activation and foam cell formation, reducing the release of pro-inflammatory factors, and inhibiting proliferation of vascular smooth muscle cells, an anti-atherosclerosis effect is exerted (Yin y., et al, eur.j. Pharmacol.,2013, 699, 219-226); reducing the risk of hyperlipidemia by promoting the sulfur transfer pathway to reduce homocysteine (Hcy) levels, maintaining redox balance; the release of the vasodilator is promoted, the partial opening of the potassium channel and the inhibition of the calcium channel play a role in vasodilating blood vessels, so that the hypertension is improved; the injury of inflammatory factors, free radicals and the like to cells is reduced through the functions of antioxidation, anti-inflammation, anti-apoptosis and the like, the homeostasis of endothelial cells is maintained, and the endothelial cells are protected; by promoting proliferation of peripheral blood Endothelial Progenitor Cells (EPCs), and significantly improving the adhesion, migration and proliferation capacity of cells, it is involved in repair of vascular intima injury in vivo (Yin y., et al, eur. J. Pharmacol.,2017, 814, 274-282). In recent years, tanshinol also has an anti-osteoporosis effect, or an effect of affecting bone metabolism: the salvianic acid A can promote the differentiation of mesenchymal stem cells to osteoblasts, promote the proliferation of the osteoblasts, enhance the functions of the osteoblasts, promote the mineralization of the osteoblasts, inhibit the osteoclast and reduce the bone resorption; promoting bone formation, promoting callus formation, resisting osteoporosis, or affecting bone metabolism, etc. (Yang y.j., et al, oxid. Med. Cell longev.,2013,1-18; luo s.y., et al, j. Orthop. Fransl., 2016,4, 35-45).
The salvianic acid A structure contains an ortho-diphenol hydroxyl group and a phenyllactic acid structure, has extremely poor fat solubility, is unstable in structure and is easy to oxidize (particularly in an alkaline environment, phenolic hydroxyl groups are easy to oxidize to generate colored quinone substances). The salvianic acid A is distributed in the human body, metabolized rapidly, and has an elimination half-life t1/2 of about 0.94h (about 56 min) (Liu Qi, et al, pharmaceutical, 2003,10,771-774) in a manner that may be rendered inactive by acetylation of the alpha-hydroxy group (Pei Weijing, et al, analytical chemistry, 2005, 04, 505-508). The oral salvianic acid A is difficult to absorb, has a bioavailability of only 11.09%, and is rapidly eliminated from the systemic circulation at a half-life t1/2 of 45.37min (Zhou l.m., et al, int.j.pharm.,2009,379, 109-118), which makes it difficult for the oral salvianic acid A to maintain an effective blood level in the body, often failing to achieve the desired therapeutic effect. To increase circulation time of DSS in vivo and improve oral bioavailability, salvianic acid a is prepared into phospholipid complex, and then the lipophilicity is improved, the membrane absorption of the drug is improved, and the oral bioavailability is improved (Liu Shasha, et al, university of Nanjing, university of Chinese medicine, 2014, 30, 164-167); the bioavailability of oral salvianic acid A can be increased from 11.09% to 18.62% with sodium caprate (Zhou l.m., et al, int.j.pharm.,2009,379, 109-118). Although the oral bioavailability of the DSS is improved to a certain extent, the circulation time of the DSS in the body is not improved, and the partial absorption enhancer may cause damage and irritation to intestinal mucosa. Therefore, the lipophilic salvianic acid A prodrug is designed and synthesized, the physicochemical property of the lipophilic salvianic acid A prodrug is changed, the permeation of intestinal membranes is promoted, the oral absorption of the drug is improved, the bioavailability is improved, and the aim of the expected effect of the oral drug is achieved, so that the lipophilic salvianic acid A prodrug has important significance.
Amino acids are basic substances of vital activities, have good biocompatibility, cell affinity and safety, and are widely applied in the field of pharmaceutical chemistry. A large number of experiments prove that the method for designing amino acid, amino acid derivatives and short peptide modified active monomer products or medicines can improve the solubility of a parent body, enhance the curative effect, reduce the toxic and side effects and even realize the targeting effect of the medicines. These are attributed to the fact that most oral drugs are absorbed in the small intestinal epithelium after entering the human body, and that drug molecules with oligopeptides or amino acid fragments can be preferentially targeted for recognition and absorption, containing a variety of amino acids and transporters of oligopeptides on the small intestinal epithelium chorion. Such as: the angiotensin converting enzyme inhibitors fosinopril and enalapril et al (Subbaiah m.a.m., et al, eur.J.Med.chem.,2017, 139, 865-883;Blaskovich M.A.T, J.Med.chem.,2016, 59, 10807-10836).
Based on the theory, the invention carries out structural transformation on the tanshinol compound to prepare a series of tanshinol derivatives containing amino acid, evaluates the pharmacological activity of the tanshinol derivatives on cardiovascular and cerebrovascular diseases and related diseases of orthopaedics, and aims to find effective tanshinol derivative pharmaceutical products.
Disclosure of Invention
The present invention relates to a tanshinol derivative or a pharmaceutically acceptable salt thereof, and also relates to a pharmaceutical composition comprising a tanshinol derivative and a pharmaceutically acceptable salt thereof. In addition, the invention also relates to a preparation method of the tanshinol derivative and the pharmaceutically acceptable salt thereof. Furthermore, the invention also relates to application of the tanshinol derivative in preparing medicines for preventing or treating diseases.
The tanshinol derivative provided by the invention has a structure shown in a formula (I):
Wherein,
X represents NH, O or S;
a1 and A2 are the same or different;
a1 represents an amino acid group, including naturally occurring amino acids or synthetic amino acids;
A2 represents hydrogen, an alkane or an amino acid group, the amino acid in the amino acid group comprising a naturally occurring amino acid or an artificially synthesized amino acid;
when A2 represents alkane, A2 is alkane radical containing 1-14 carbon atoms, A1 and A2 are connected by ester bond;
when A2 represents an amino acid group, A1 and A2 are linked by an amide bond to form a dipeptide structural group.
Further, when A2 represents hydrogen or an alkane, A1 is each independently a lysine, arginine, histidine, ornithine, 2, 3-diaminopropionic acid, 2, 4-diaminopropionic acid, alanine, valine, leucine, norleucine, tertiary leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, methionine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid or proline group;
When A2 represents an amino acid group, A1, A2 are each independently a lysine, arginine, histidine, ornithine, 2, 3-diaminopropionic acid, 2, 4-diaminopropionic acid, alanine, valine, leucine, norleucine, tertiary leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, methionine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid or proline group.
Further, A2 is a substituted or unsubstituted C1-C6 alkyl group, a C3-C8 cycloalkyl group, or a substituted or unsubstituted 4-to 8-membered heterocyclic group.
Further, the amino acid is D-form, L-form or DL-form.
Further, in the structure of formula I, when X represents NH, the tanshinol derivative is an amide formed by condensing carboxyl of tanshinol and amino of amino acid, and has a structure shown in formula (II):
Further, in the structure of formula I, when X represents O, the tanshinol derivative is an ester formed by esterifying carboxyl of tanshinol with hydroxyl of amino acid containing hydroxyl, and has a structure shown in formula (III):
further, the hydroxyl-containing amino acid is serine, threonine or tyrosine;
wherein R1 represents H, acetyl, propionyl, isobutyryl, butyryl, pivaloyl, pentanoyl and isovaleryl.
Further, in the structure of formula I, when X represents S, the tanshinol derivative is a sulfhydryl ester formed by esterification of carboxyl of tanshinol and sulfhydryl containing sulfhydryl amino acid, and has a structure shown in formula (IV):
Further, the sulfhydryl-containing amino acid is cysteine.
Wherein R2 represents H, acetyl, propionyl, isobutyryl, butyryl, pivaloyl, pentanoyl and isovaleryl.
Further, the tanshinol derivative is one of the following compounds:
The invention also provides a method for preparing the tanshinol derivative, which comprises the following steps: taking tanshinol as a raw material, and carrying out condensation reaction or esterification reaction with amino acid or dipeptide containing protecting group to obtain the tanshinol derivative shown in the formula I.
The specific synthetic route is as follows:
i condensation reaction
Dissolving compound 1 sodium salvianic acid A in an organic solvent, adding a condensing agent and organic base, mixing and stirring, adding carboxyl-protected amino acid or dipeptide to perform condensation reaction, and performing post-treatment and column chromatography separation and purification on a sample after the reaction is finished to obtain the compound shown in the formula II.
Further, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, acetone, N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like.
Further, the condensing agent is N, N ' -Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), N-dimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxyphenylpropanetriazole (HOBt), N-hydroxysuccinimide (NHS), 2- (7-benzotriazol) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), O-benzotriazol-tetramethylurea Hexafluorophosphate (HBTU), benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and similar functional condensing agents.
Further, the organic base is methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, diisopropylethylamine or triethylamine.
Further, the carboxyl protecting groups of the carboxyl protected amino acid are tert-butyl ester, isopropyl ester, ethyl ester, methyl ester, benzyl ester and other chemically similar functional groups.
Further, the temperature of the condensation reaction is-20 ℃ to 50 ℃, and the salvianic acid A sodium is: condensing agent: organic base: carboxyl protected amino acids or dipeptides: the molar ratio of the organic solvent is 1:1-2:1-3:1-3:5-50; the reaction time is 0.5h-30h.
Ii esterification reaction
Protecting phenolic hydroxyl and alcoholic hydroxyl of sodium salvianic acid A of a compound 1, dissolving a compound 2 with hydroxyl protection in an organic solvent, adding a catalyst, mixing and stirring, adding hydroxyl-containing amino acid, sulfhydryl-containing amino acid or dipeptide for esterification, removing hydroxyl protection, separating and purifying to obtain a compound shown in a formula III or a formula IV.
Further, the hydroxyl protection is an acyl or hydrocarbyl protection.
Further, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, acetone, N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like.
Further, the catalyst is N, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 4-Dimethylaminopyridine (DMAP) and similar functional catalysts.
Further, the temperature of the esterification reaction is-20 ℃ to 50 ℃, and the compound 2: catalyst: amino acid or dipeptide: the molar ratio of the organic solvent is 1:1-3:1-3:5-50, and the reaction time is 0.5-30 h.
The invention also provides a pharmaceutical composition, which comprises the tanshinol derivative or the pharmaceutically acceptable salt thereof with pharmaceutically effective dose and a pharmaceutically acceptable carrier.
The invention also provides the tanshinol derivative and pharmaceutically acceptable salt thereof, and application of the corresponding pharmaceutical composition in preparing medicines for treating cardiovascular and cerebrovascular diseases.
Further, the cardiovascular and cerebrovascular diseases comprise hypertension, coronary heart disease, myocardial infarction, atherosclerosis, angina pectoris, thrombosis, myocarditis, cerebral apoplexy, arrhythmia, heart failure, cerebral hemorrhage, cerebral embolism, rheumatic heart disease, infectious heart disease, and anemia heart disease.
The invention also provides the tanshinol derivative and pharmaceutically acceptable salt thereof, and application of the corresponding pharmaceutical composition in preparing medicines for treating orthopedic diseases.
Further, the orthopedic disorder is selected from the group consisting of osteoporosis, fracture healing disorders, fractures, bone defect repair, ectopic ossification, hyperosteogeny, bone/arthritis, bone/joint pain, and the like.
Further, the bone disease is osteoporosis and/or a fracture healing disorder.
Compared with the prior art, the invention has the beneficial effects.
The preparation method is reasonable in design, easy to synthesize, most of the compounds have new chemical structures, and in vitro cell activity experiments prove that most of the synthesized amino acid derivatives have very obvious myocardial cell and osteoclast protection effects, and part of the compounds have stronger activity than the salvianic acid, so that the salvianic acid can be applied to the preparation of medicaments for protecting, treating and/or relieving cardiovascular and cerebrovascular diseases of patients and orthopedic diseases, and a new therapeutic medicament is provided for preventing and treating the cardiovascular and cerebrovascular diseases and the orthopedic diseases.
Drawings
FIG. 1 is a graph showing the protective effect of a tanshinol derivative on t-BHP-induced myocardial cell injury in example 9; where n=3. ## P <0.01 compared to normal control; p <0.05, < P <0.01 compared to the hypoxic injury group.
FIG. 2 is a graph showing the results of the detection of bone density in DA-03 treated ovariectomized osteoporosis rats in example 9; where n=6. P <0.05, < P <0.01 compared to control group; a P <0.05 compared to the positive control group; ## P <0.01 compared to sham.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The term "pharmaceutically acceptable" as used herein means having no unacceptable toxicity in a compound such as a salt. Pharmaceutically acceptable salts include inorganic anions such as chloride, sulfate, sulfite, nitrate, nitrite, phosphate, hydrogen phosphate, and the like. The organic anions include acetate, propionate, cinnamate, benzoate, citrate, lactate, gluconate, and the like.
The tanshinol derivative of the present invention may be administered to a patient in the form of a pharmaceutically acceptable salt or pharmaceutical composition. A complex is formulated with a suitable carrier or excipient to form a pharmaceutical composition to ensure that a therapeutically effective dose is achieved. "effective therapeutic dose" refers to the dose of the tanshinol derivative necessary to achieve a therapeutic effect.
The tanshinol derivative and the composition containing the compound can be prepared into various dosage forms, including solid dosage forms, semisolid dosage forms, liquid preparations and aerosols (Remington's Pharmaceutical Sciences, mack Publishing Company (1995), philadelphia, PA,19th ed). Specific dosage forms of these several types of dosage forms include tablets, pills, dragees, granules, gels, ointments, solutions, suppositories, injections, inhalants and sprays. These dosage forms can be used for both local or systemic administration and for immediate or sustained release administration.
When the tanshinol derivatives and the compositions containing these compounds are administered by injection, the compounds can be formulated into solutions, suspensions and emulsions with water-soluble or fat-soluble solvents. The fat-soluble solvent includes vegetable oil and similar oils, synthetic fatty acid glyceride, higher fatty acid ester and glycol ester (proylene glycol). Such compounds are more soluble in ethanol solutions and in trace amounts of DMSO.
When the tanshinol derivative and the composition containing the compound are orally administered, it can be formulated into a complex with a pharmaceutically acceptable excipient using a common technique. These excipients can be used to prepare a variety of dosage forms for patients, such as tablets, pills, suspensions, gels, and the like. The preparation of oral preparation is carried out by mixing compound with solid excipient, grinding mixture, adding adjuvant, and granulating. Adjuvants which can be used for preparing oral dosage forms include: sugars such as lactose, sucrose, mannitol, or sorbitol; celluloses such as corn starch, wheat starch, potato starch, gelatin, huang Shujiao, methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, etc.
The tanshinol derivatives and the compositions containing the compounds can also be prepared into spray, and the preparation is realized by a pressurizer and a sprayer or a dry powder inhalation device. Can be used as a suitable propellant in the ejector, such as dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide, dimethyl ether and the like. The dose of aerosol administration may be regulated by the valve of the injector.
The various dosage forms to which the present invention relates relate to therapeutically effective doses of tanshinol derivatives and compositions containing these compounds. The effective therapeutic dose of such compounds depends on the patient being treated. The weight of the patient, the condition of the patient, the mode of administration, and the subjective judgment of the prescribing physician are all factors considered in determining the appropriate dosage. The therapeutically effective amounts of the tanshinol derivatives and compositions containing these compounds should be determined by a prescribing physician with the ability and great experience.
Although the therapeutically effective dose of the tanshinol derivatives and the compositions containing these compounds will vary depending on the condition of the patient, the appropriate dosage range is usually 10mg to 10g.
EXAMPLE 1 Synthesis of Compound DA-01
The specific synthesis is as follows:
Sodium danshensu (200 mg,0.909 mmol) and 8ml anhydrous N, N-Dimethylformamide (DMF) were added to a 25ml single neck round bottom flask and stirred at room temperature. To this was added, in order, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl) (260 mg,1.36 mmol), 1-Hydroxybenzotriazole (HOBT) (184 mg,1.36 mmol), N-Diisopropylethylamine (DIPEA) (470 mg,3.636 mmol), and the mixture was activated at room temperature for 1 hour. Finally, L-glutamic acid dimethyl ester hydrochloride (230 mg,1.09 mmol) was added to the reaction system, and the reaction was stirred at room temperature and terminated after 18 hours. 10ml of water was added to the reaction system, the pH was adjusted to 5 with 1M diluted hydrochloric acid, extraction was performed 3 times with ethyl acetate (50 ml. Times.3), and the organic phase was washed with saturated NaCl. The organic phase was dried over anhydrous Na 2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel (100-200 mesh), with the developing solvent (petroleum ether: ethyl acetate=1:1→dichloromethane: methanol=20:1) to give 131mg of the white target product in 70.6% yield.
DA-01 corresponds to the compound of the formula I, X represents NH, A1 represents glutamate and A2 represents methyl.
1 H NMR data are as follows ：1H NMR(CDCl3,300MHz)δ:2.00(t,1H,J＝6.5Hz),2.20(t,1H,J＝6.2Hz),2.35-2.39(m,2H),2.98(t,2H,J＝5.2Hz),3.69(s,3H),3.76(s,3H),4.28(s,1H),4.60(dd,1H,J＝8.0,13.3Hz),5.72(s,1H),6.66(d,1H,J＝7.8Hz),6.73(s,1H,),6.83(d,1H,J＝7.9Hz);
13 C NMR data are as follows ：13C NMR(CDCl3,75MHz)δ:27.16,29.70,39.80,52.11,52.76,53.43,72.49,115.36,116.44,122.13,143.63,143.87,172.09,173.50.
EXAMPLE 2 Synthesis of Compound DA-02
The same procedure as in example was repeated except that the methyl L-glutamate hydrochloride used in example was changed to methyl L-norleucine hydrochloride to obtain a white solid powder in 73.5% yield.
DA-02 corresponds to the compound of the formula I, X represents NH, A1 represents norleucine and A2 represents methyl.
1 H NMR data are as follows ：1H NMR(CDCl3,300MHz)δ:0.87(t,3H,J＝6.2Hz),1.25(s,2H),1.28(s,2H),1.67(s,1H),1.79(s,1H),2.82(s,1H),2.97-3.05(m,1H),3.72(s,1H),4.25(s,1H),4.54(d,J＝4.4Hz),5.30(s,1H),6.60(s,1H),6.76(s,1H),7.16(d,1H,J＝6.1Hz);
13 C NMR data are as follows ：13C NMR(CDCl3,75MHz)δ:13.80,22.21,27.44,31.81,39.87,52.13,52.60,72.73,115.41,116.42,121.85,128.40,143.49,144.02,173.14.
EXAMPLE 3 Synthesis of Compound DA-03
The same procedure as in example was repeated except that the methyl L-glutamate hydrochloride used in example was changed to methyl L-tert-leucine hydrochloride to give a white solid powder in a yield of 65.9%.
DA-03 corresponds to the compound of the formula I, X represents NH, A1 represents tert-leucine and A2 represents methyl.
1 H NMR data are as follows ：.1H NMR(CDCl3,300MHz)δ:0.96(s,9H),2.78-2.85(m,1H),2.97-3.03(m,1H),3.71(s,3H),4.26(dd,1H,J＝4.0,7.3Hz),4.24(d,1H,J＝9.3Hz),6.59(d,1H,J＝7.8Hz),6,70(s,1H),6.77(d,1H,J＝8.1Hz),7.19(d,1H,J＝9.2Hz);
13 C NMR data are as follows ：13C NMR(CD3OD,75MHz)δ:25.40,34.11,39.58,51.05,59.86,72.41,114,64,116.43,120.68,128.48,143.51,144.50,170.93,174.55.
EXAMPLE 4 Synthesis of Compound DA-04
The same procedure as in example was repeated except that the methyl L-glutamate hydrochloride used in example was changed to L-leucine methyl ester hydrochloride to obtain a white solid powder in a yield of 81.5%.
DA-04 corresponds to the compound of the formula I, X represents NH, A1 represents leucine and A2 represents methyl ester.
1 H NMR data are as follows ：1H-NMR(CDCl3,300MHz)δ:0.93(d,6H,J＝5.1Hz),1.26(s,1H),2.05(s,1H),3.03(d,2H,J＝5.1Hz),3.75(s,3H),4.32(t,1H,J＝5.0Hz),4.61(s,1H),6.64(d,1H,J＝8.7Hz),6.76(s,1H),6.83(d,1H,J＝7.8Hz),6.88(d,1H,J＝8.9Hz);
13 C NMR data are as follows ：13C-NMR(CD3OD,75MHz)δ:20.47,21.87,24.38,39.90,40.30,50.28,51.37,72.83,114.69,116.33,120.53,128.77,143.53,144.59,172.91,174,94.
EXAMPLE 5 Synthesis of Compound DA-05
The same procedure as in example was repeated except that the dimethyl L-glutamate hydrochloride used in example was changed to dimethyl L-aspartate hydrochloride to obtain a white solid powder in 73.1% yield.
DA-05 corresponds to the compound of the formula I, X represents NH, A1 represents aspartic acid, A2 represents methyl ester.
1 H NMR data are as follows ：1H NMR(CDCl3,300MHz)δ:2.81(d,2H,J＝14.9Hz),2.97-3.03(m,2H),3.66(s,3H),3.72(s,3H),4.26(s,1H),4.85(t,1H,J＝3.9Hz),6.59(d,1H,J＝8.9Hz),6.75(s,2H),7.56(d,1H,J＝7.9Hz);
13 C NMR data are as follows ：13C NMR(CDCl3,75MHz)δ:35.97,39.81,52.31,53.06,72.70,115.42,116.45,121.96,128.40,143.44,143.91,171.09,171.54,173.62.
EXAMPLE 6 Synthesis of Compound DA-06
The same procedure as in example was repeated except that L-glutamic acid dimethyl ester hydrochloride used in example was changed to L-methionine methyl ester hydrochloride to obtain white solid powder in 79.6% yield.
DA-06 corresponds to the compound of the formula I, X represents NH, A1 methionine, A2 represents methyl ester.
1 H NMR data are as follows ：1H NMR(CDCl3,300MHz)δ:2.04(s,6H),2.34(s,2H),2.81(s,1H),3.00(d,1H,J＝12.4Hz),3.72(s,3H),4.28(s,1H),4.68(s,1H),6.59(d,1H,J＝7.0Hz),6.72-6.78(m,2H),7.38(d,1H,J＝6.4Hz);
13 C NMR data are as follows ：13C NMR(CDCl3,75MHz)δ:15.26,29.72,31.14,39.80,51.18,52.85,72.81,115.57,116.65,121.97,128.87,143.23,143.92,172.60.
EXAMPLE 7 Synthesis of Compound DA-12
The same procedure as in example was repeated except that the dimethyl L-glutamate hydrochloride used in example was changed to dipeptide methyl ester hydrochloride to obtain white solid powder in a yield of 68.0%.
DA-12 corresponds to the compound of the formula I, X represents NH, A1 represents glycine and A2 represents tert-leucine.
1 H NMR data are as follows ：1H NMR(CDCl3,300MHz)δ:0.92(s,9H),2.92-3.06(m,2H),3.64(s,3H),4.09(s,2H),4.15(s,1H),4.59-4.62(m,1H),6.73-6.80(m,2H),7.36(d,1H,J＝6.3Hz);
13 C NMR data are as follows ：13C NMR(CDCl3,75MHz)δ:26.23,34.72,40.39,43.71,51.25,64.57,72.86,115.58,116.83,122.01,129.27,143.91,144.02,170.49,171.76,172.60.
EXAMPLE 8 Synthesis of Compound DA-21
The specific synthesis is as follows:
(1) Synthesis of hydroxy-protected danshensu BnDSS
3G of sodium salvianic acid A is added into 60mL of acetone/dichloromethane (4:1) mixed solution, 12g of anhydrous potassium carbonate is added, stirring is carried out for 15min, 7mL of benzyl bromide is slowly added dropwise, heating is carried out until reflux reaction is carried out for 12h, after the reaction is finished, the solvent is removed under reduced pressure, 200mL of water is added, extraction is carried out with ethyl acetate (3X 200 mL), the combined organic phases are washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a pale yellow solid. Directly dissolving in 100mL tetrahydrofuran/water (4:1) mixed solution, adding 0.7g of potassium hydroxide, heating and refluxing for reaction for 2h, removing solvent under reduced pressure after the reaction is finished, separating and purifying by a direct silica gel (100-200 meshes) chromatographic column, and separating a developing agent (petroleum ether: ethyl acetate=4:1) to obtain 4.3g of a white target product with the yield of 87.3%. Mass spectrometry results ESI-MS: m/z 4637 [ M-H ] -.
(2) Synthesis of target Compound DA-21
BnDSS (400 mg,0.8 mmol) and N-acetyl-L-serine methyl ester (200 mg,1.2 mmol) were dissolved in 10mL dichloromethane, DCC (230 mg,1.2 mmol) and DMAP (12 mg,0.08 mmol) were added under stirring at room temperature and stirred at room temperature for 8h, after the reaction was completed, the solvent was removed under reduced pressure, and the column was purified by direct silica gel (100-200 mesh) chromatography with developing solvent (petroleum ether: ethyl acetate=4:1) to give the white target product.
Deprotection: dissolving the prepared tanshinol amino acid ester containing the protecting group in 10mL of methanol, adding 20mg of 10% palladium-carbon, introducing hydrogen, vigorously stirring for 6h at room temperature, filtering with diatomite to remove the catalyst, and concentrating under reduced pressure to obtain 238mg of target product with a yield of 72.7%.
DA-21 corresponds to the compound of the formula I, X stands for O, A for serine and A2 for methyl ester.
1 H NMR data are as follows ：1H NMR(CDCl3,300MHz)δ:1.88(s,3H),2.81(dd,J＝8.2,3.8Hz,1H),3.00(dd,J＝8.2,3.9Hz,1H),3.67(s,3H),4.19(dd,J＝6.9,3.6Hz,1H),4.27(dd,J＝6.9,3.6Hz,1H),4.52-4.59(m,1H),4.79-4.82(m,1H),6.71-6.76(m,2H),7.37(d,1H,J＝6.3Hz);
13 C NMR data are as follows ：13C NMR(CDCl3,300MHz)δ:20.53,39.91,51.21,52.69,63.12,71.81,115.43,116.72,122.05,129.14,143.98,144.62,169.97,170.05,171.70.
EXAMPLE 9 protective Effect of Compounds DA-01, DA-02, DA-03, DA-04, DA-05, DA-06, DA-12 and DA-21 on t-BHP-induced myocardial cell injury
The cultured myocardial cells are randomly divided into a normal control group, an anoxic damaged group, 100 mu M sodium salvianic acid A and 5-500 mu M salvianic acid A amino acid derivatives with different concentrations, and 5 groups are arranged. HUVEC cells were seeded at a density of 1X 104 cells per well in 96-well plates, incubated in incubator at 37℃until the cells grew to 70% -80%, drug-protected 24h was added according to experimental group, 100. Mu.L of 150. Mu. M t-BHP was added to stimulate each well for 2h (normal control group was not stimulated with t-BHP), prepared CCK-8 working solution was added, 100. Mu.L/well was incubated at 37℃for 1h. And detecting the absorbance value of each hole at the wavelength of 450nm by using an enzyme-linked immunosorbent assay instrument, and calculating the cell survival rate. Cell viability (%) = absorbance of sample group/absorbance of blank group x 100%.
The experimental results are shown in FIG. 1. The control group was compared with the hypoxia injury group, and the hypoxia injury group was lower than the control group (P < 0.01). Compared with the anoxic injury group, the higher difference of the danshensu amino acid derivative above 100 mu M group has significance (P < 0.05).
EXAMPLE 10 DA-03 investigation of the Effect of MC3T3-E1 osteoblast Activity
MC3T3-E1 osteoblasts were seeded into 96-well plates at a density of 2X 10 4 cells/well and after 24h incubation, the drug-containing medium was replaced according to experimental groups. After 72h, the cells were cultured in each well and washed 1 time with PBS, 100. Mu.L of DMEM medium was added to each well, 10. Mu.L of 5mg/mL of tetramethylazoblue (MTT) was added simultaneously, and after further culturing for 4h, 100. Mu.L of dimethyl sulfoxide was added to each culture well supernatant, and the cells were dissolved by shaking for 10min, OD was measured at 470nm wavelength with an ELISA reader, and proliferation rate was calculated.
The experimental results are shown in Table 1. Compared with the control group, the 100 mu M danshensu derivative DA-03 group has obvious proliferation promoting effect (P < 0.01), the 50 mu M danshensu derivative DA-03 group and the 200 mu M danshensu derivative DA-03 group have proliferation promoting effect (P < 0.05), and the 5 mu M danshensu derivative DA-03 group and the 500 mu M danshensu derivative DA-03 group have no proliferation promoting effect (P > 0.05).
TABLE 1 Effect of danshensu amino acid derivative DA-03 on MC3T3-E1 osteoblast proliferation
Comparing P with 0.05; * P < 0.01 compared to control group.
EXAMPLE 11 DA-03 therapeutic Effect on treatment of ovariectomized osteoporosis rats
(1) Experimental materials
Animals: clean-class adult female SD rats 42, with a body mass of 250-300g, supplied by Shanghai Laike laboratory animal Co. License number: SCXK (Shanghai) 2017-0005. The animals are kept in separate cages in an air-conditioning greenhouse, the temperature is 21+/-1 ℃ and the humidity is 50-60%, and the animals are fed with pellet feed and drink water freely.
(2) Experimental method
Grouping animals
Grouping animals: the experiment was divided into 7 groups of 6 rats each, namely four groups of DA-03 (10 mg/kg, 20mg/kg, 50mg/kg, 100 mg/kg), control group, positive control group and sham operation group. Each of the experimental groups DA-03 was given a corresponding dose (10, 20, 50, 100 mg/kg) for 1 time/d of intragastric administration; the control group is irrigated with purified water with the same amount; the positive control group was fed with 0.02mg/kg of dienestrol for gastric lavage, 1 time/d; the stomach of the sham operation group is irrigated with purified water with equal quantity. All rats were on daily diet and the survival environment was kept consistent for 8 weeks.
The molding method comprises the following steps: a model of osteoporosis was established by ovariectomy, rats in each group were anesthetized by intraperitoneal injection of 350mg/kg of 10% chloral hydrate, an incision of 1.5cm in size was made in the abdomen, abdominal muscles were isolated, the peritoneum was vented, and the bilateral ovaries were removed after cutting the peritoneum. The false operation group will not do any treatment after cutting the abdomen, suture the wound and disinfect; the operation group is used for cutting off and suturing the wound after the ligation of the ovaries at both sides, and sterilizing.
Rat bone density detection each group of rats at weeks 4 and 8 of the experiment were anesthetized with 1% sodium pentobarbital, and after anesthesia, placed in a bone density detector to detect femur bone density of each group.
(3) Statistical treatment
The SPSS 13.0 statistical software is adopted, the independent sample T test is adopted for the pairwise comparison, the single-factor analysis of variance is adopted for the comparison among the averages of a plurality of samples, and the P <0.05 has statistical significance
(4) Rat bone density detection result
As shown in FIG. 2, ① compared with the control group, the bone density of the three groups of rats of DA-03 (20 mg/kg, 50mg/kg, 100 mg/kg) was higher (P < 0.05) at week 4,8, and the difference of DA-03 (10 mg/kg) was not significant (P > 0.05); ② Compared with the positive control group, the bone density of two groups of rats of DA-03 (10 mg/kg, 20 mg/kg) is lower (P < 0.05) at 4,8 weeks, and the bone density difference of two groups of rats of DA-03 (50 mg/kg, 100 mg/kg) has no significance (P > 0.05); ③ The control group and the sham group were compared, and the bone density of the control group rats was lower at both week 4 and week 8 (P < 0.05).
Claims (9)
1. A tanshinol derivative and pharmaceutically acceptable salts thereof, wherein the tanshinol derivative has a structure shown in a formula I:
Wherein,
X represents NH, O or S;
a1 and A2 are the same or different;
A1 represents an amino acid group;
a2 represents an alkane or amino acid group;
when A2 represents alkane, A2 is alkane radical containing 1-14 carbon atoms, A1 and A2 are connected by ester bond;
When A2 represents an amino acid group, A1 and A2 are linked by an amide bond to form a dipeptide structural group;
When A2 represents an alkane, A1 is a lysine, arginine, histidine, ornithine, 2, 3-diaminopropionic acid, tertiary leucine, tryptophan, serine, threonine, glutamine or proline group;
When A2 represents an amino acid group, A1, A2 are each independently a lysine, arginine, histidine, ornithine, 2, 3-diaminopropionic acid, valine, leucine, norleucine, tertiary leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid or proline group.
2. The tanshinol derivative according to claim 1, characterized in that: the amino acid is D-type, L-type or DL-type.
3. The method for producing a tanshinol derivative according to claim 1 or 2, comprising:
i condensation reaction
Dissolving compound 1 sodium salvianic acid A in an organic solvent, adding a condensing agent and organic base, mixing and stirring, adding carboxyl-protected amino acid or dipeptide to perform condensation reaction, and performing post-treatment and column chromatography separation and purification on a sample after the reaction is finished to obtain a compound shown in a formula II; wherein the temperature of the condensation reaction is-20 ℃ to 50 ℃, and the salvianic acid A sodium is: condensing agent: organic base: carboxyl protected amino acids or dipeptides: the molar ratio of the organic solvent is 1:1-2:1-3:1-3:5-50; the reaction time is 0.5h-30h;
Or ii esterification reaction
Protecting phenolic hydroxyl and alcoholic hydroxyl of sodium salvianic acid A of a compound 1, dissolving a compound 2 with hydroxyl protection in an organic solvent, adding a catalyst, mixing and stirring, adding hydroxyl-containing amino acid, sulfhydryl-containing amino acid or dipeptide for esterification, removing hydroxyl protection, separating and purifying to obtain a compound shown in a formula III or a formula IV; wherein the temperature of the esterification reaction is-20 ℃ to 50 ℃, and the compound 2: catalyst: amino acid or dipeptide: the molar ratio of the organic solvent is 1:1-3:1-3:5-50, and the reaction time is 0.5-30 h.
4. A method of preparation according to claim 3, characterized in that: the carboxyl protecting group of the carboxyl-protected amino acid is a tert-butyl ester, isopropyl ester, ethyl ester, methyl ester or benzyl ester group; the hydroxyl protection is acyl or hydrocarbyl protection.
5. A pharmaceutical composition comprising the tanshinol derivative of any of claims 1-2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. Use of a tanshinol derivative according to any of claims 1-2 and a pharmaceutically acceptable salt thereof for preparing a medicament for treating cardiovascular and cerebrovascular diseases.
7. The use according to claim 6, characterized in that: the cardiovascular and cerebrovascular diseases are hypertension, coronary heart disease, myocardial infarction, atherosclerosis, angina pectoris, thrombosis, myocarditis, cerebral apoplexy, arrhythmia, heart failure, cerebral hemorrhage, cerebral embolism, rheumatic heart disease, infectious heart disease or anaemia heart disease.
8. Use of a tanshinol derivative according to any of claims 1-2 and a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an orthopedic disorder.
9. The use according to claim 8, characterized in that: the bone diseases are osteoporosis, fracture healing disorder, fracture, bone defect repair, ectopic ossification, hyperosteogeny, bone/arthritis or bone/joint pain.
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| 丹参素-氨基酸酰胺类衍生物的合成及初步药理学研究;高永飞;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》(第02期);第E057-331页 * |
| 高永飞.丹参素-氨基酸酰胺类衍生物的合成及初步药理学研究.《中国优秀硕士学位论文全文数据库 医药卫生科技辑》.2017,(第02期),第E057-331页. * |
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